TWI345566B - Motilide polymorphs - Google Patents

Description

1345566 IX. DESCRIPTION OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention relates to polymorphic forms of activating lactones, and to methods and uses for the preparation of such polymorphs. [Prior Art]

The gastrointestinal ("Gastrointestinal, GI") snail regulates the ingestion of the substance regularly in the digestive tract to ensure adequate absorption of nutrients, electrolytes and fluids. The proper passage of the GI contents through the esophagus, stomach, small intestine, and colon is dependent on regional control of intraluminal pressure and several sphincters, thereby regulating its forward motion and preventing backflow. The normal GI peristaltic pattern can be compromised by various conditions including illness and surgery. GI screw disorders include gastroparesis and gastroesophageal reflux disease (GERD). Gastroparesis refers to delayed emptying of gastric contents, including stomach upset, heartburn, beta nausea, and vomiting. GERD refers to various clinical manifestations of the contents of the stomach and duodenum flowing back into the esophagus. The most common symptoms are heartburn and dysphasia, which is also known to cause blood loss caused by esophageal invasion. Other examples of GI disorders involving attenuated GI peristalsis include anorexia, gall bladder stasis, postoperative paralytic ileus, scleroderma, pseudo-intestinal obstruction ( Intestinal pseudo-obstruction), irritable bowel syndrome, gastritis, ° vomiting and chronic constipation (colonic inertia) ° Motilin is secreted by endocrine cells in the intestinal mucosa 22 126639.doc 1345566 Amino acid hormone. It binds to the enterin receptor in the GI tract and stimulates to sway. Administration of a therapeutic agent acting as a parenteral agonist ("pr〇kinetic agent") has been proposed as a treatment for GI disorders. Erythromycin is a family of vinegar antibiotics produced by the actinomycetes of the actinomycete. Erythromycin A, often used as an antibiotic, is the most abundant and important member of this family.

(1) Erythromycin A Ra=〇H, Rb=Me (2) Erythromycin B Ra=H, Rb=Me (3) Erythromycin C Ra=OH, Rb=n

(4) Erythromycin D Ra = H, Rb = H Side effects of erythromycin A include nausea, vomiting and abdominal discomfort. These effects have been traced back to the enteratin agonist activity in erythromycin A (1), and in particular

Its initial acid catalyzed degradation product (5). (Secondary degradation product snail ketal (6) inactive) 〇

126639.doc 1345566

Inspired by the discovery of enterin agonist activity in erythromycin A and degradation product 5, researchers have sought to discover new activator lactones, also known as macrolides with peristaltic promoting activity. Numerous studies have focused on the production of new erythromycin analogs via post-fermentation chemical transformation of natural erythromycin or through improvements in genetic engineering, including genetic engineering. Illustrative disclosures of actuating lactones include: US 5,008,249 (1991) to Omura et al. and US 5,175,150 (1992); US 5,470,961 (1995) to Harada et al.; US 5,523,401 to Freiberg et al. ), US 5,523,418 (1996), US

5, 538, 961 (1996) and US 5, 554, 605 (1996); US 5, 578, 579 (1996), US 5, 654, 411 (1997), US 5, 712, 253 (1998), and US 5, 834, 438 (1998); Koga et al. US 5,959,088 (1998) to Miura et al.; US 5,922,849 (1999) to Premchandran et al; US 6,084,079 (2000) to Keyes et al; US 2002/0025936 A1 (2002) to Ashley et al., US 2002/ Ashley et al. 0094962 A1 (2002); Carreras et al. λ US 2002/0192709 Α 1 (2002); Ito et al. JP 60-218321 (1985) (corresponding Chemical Abstracts No. 104:82047); Santi et al. US 2004/138150 A1 (2004); Carreras et al. US 2005/0113319 c S ) 126639.doc 1345566 A1 (2005); Carreras et al. US 2005/0119195 A1 (2005); Liu #乂之US 2005/0256064 A1 (2005) Omura et al., 乂 1985, 38, 1631-2; Faghih et al., ά Med. C/iew. Ze"., 1998, 8, 805-810; Faghih et al., 乂C/zem., 1998, 41 , 3402-3408; Faghih et al, Jul. 1998, 751; and Lartey et al., / Med. C/zem., 1995, 38, 1793-1798. The disclosures of all of the aforementioned documents are incorporated herein by reference.

There are also potentially related other erythromycin backbone compounds (even if not intended to be an enterin agonist), illustrative disclosures include: Krowicki # 乂 US 3,855,200 (1974); Radobolja et al. US 3,939,144 (1976) US 3,983,103 (1976) to Kobrehel et al; US 4,588,712 (1986) to Toscano; US 5,444,051 (1995) to Agouridas et al; US 5,561,118 (1996) to Agouridas et al; US 5,770,579 (Agouridas #乂1998); Asaka et al., US 6,169,168 B1 (2001); Kobrehel et al., DE 2,402,200 (1974); Pliva Pharmaceuticals, GB 1,416,281 (1975); Pliva

Pharmaceuticals, GB 1,46 1,032 (1977); Asaga, JP 2002/241391 (2002); Ryden et al., Med. Chemistry, 1973, 16 (9), 1059-1060; Naperty et al. , /ioczwzf CTzem", 1977, 51 (6), 1207-10; Kobrehel et al., five wr «/. Med. Less, 1978, 13 (1), 83-7; Egan et al., 乂 1978, 31 ( 1), 55-62; Matijasevic et al., C/iemica 1980, 53 (3), 51'9-24; Radobolja et al., 126639.doc 1345566 by (10) heart 1985, 58 (7), 219-25; Hunt et al. , j plus café' 1989, 42 (2), 293_298; Human Heart C Team, 1990, 55, 1636_1648 β The disclosures of all of the aforementioned documents are hereby incorporated by reference. Those skilled in the art will appreciate that there are many parameters associated with the development of activator lactones. • First, the evolution of the erythromycin backbone in naturally occurring organisms has been driven by antibacterial efficacy rather than by peristaltic effects. Therefore, there is still considerable room for optimization in the structure-activity relationship of the enterin agonist. Second, % does not actually desire to activate the lactone to have antibacterial activity. The GI tract is a host of a large number of bacteria, and the exposure of the GI tract to the activic lactone having antibacterial activity may induce the development of erythromycin antibiotic resistance in bacteria. Alternatively, an activator with antibacterial activity may kill beneficial digestive tract bacteria. Therefore, it is desirable to mobilize the lactone to have an enhanced peristaltic promoting activity and an antibacterial activity which is designed to be excluded. Third, the drawbacks commonly found in priming lactones evaluated to date are that they tend to desensitize the activator lactone receptor, which means that after the initial dose, the subsequent dose of the activator lactone causes a weaker reaction or No response (tachyphylaxis). Fourth, stability and bioavailability are concerns - erythromycin A has been rapidly degraded in the stomach and its secondary degradation products lack activity. Fifth, it has been reported that certain compounds in the erythromycin family have poor pr〇_arrhythmic effects, including prolonged QT interval and induced ventricular heart rate irregularities. These effects need to be limited to acceptable levels. Therefore, there is still a need to develop new activator lactones to balance various performance requirements. US 2006/0270616 A1 126639.doc I345566 (2006) (hereinafter referred to as "Liu i616 Cases"), which is incorporated herein by reference, discloses that the class is actuated by the formula $ _ The vinegar family 'its" A, RB, mRE-: number. The specific compound disclosed in this application is compound (Ia), which has an eye-catching balance of actuating lactone properties.

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Once a compound is selected for development as a potential clinical candidate, consideration must be given to formulating the compound into a suitable pharmaceutical formulation. Conversely, it means that the possible existence of polymorphs must be considered. If a polymorph is present, it may have different medicinal related properties including solubility, storage stability, hygroscopicity, density, and bioavailability. During storage, a polymorph may be more or less spontaneously converted to another polymorph. As a result of this transformation, formulations designed to deliver a particular polymorph may eventually contain different polymorphs that are incompatible with the formulation. Hygroscopic polymorphs may absorb water during storage, causing errors in the weighing operation and affecting handleability. Preparation procedures designed for a particular polymorph may not be applicable to different multiples. Even if no mutual transformation occurs, one polymorph may be blended with another, and the choice of polymorph is critical. Thus 'polymorphic selection' is an important factor in the design of pharmaceutical formulations. (As used herein, the term "polymorph" includes both amorphous and non-soluble 126639.doc

(S -11 - 1345566 non-solvated crystalline form and s〇ivated crystalline form, as in the ICH (International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use) Guide Q6A (2) t specified by). SUMMARY OF THE INVENTION The present invention is directed to polymorphs of compound 13 that are particularly desirable for use in pharmaceutical formulations.

When prepared according to the Liu '616 application, compound la, which is not the most preferred form for formulation development (this form is designated herein as polymorph, see Example 3 below), is obtained. We have found that other polymorphs of compound ja, including one polymorph having improved properties for pharmaceutical formulations (herein referred to as polymorphs designated as polymorphs), are also useful for Suitable properties of the pharmaceutical formulation. Thus, in one embodiment, the invention provides a purified polymorph IV of compound la. In another embodiment, the invention provides a purified polymorph η of compound la.

In still another embodiment, the present invention provides a method for preparing a purified polymorph IV of a compound, wherein the method comprises: in a method selected from the group consisting of diisopropyl ether (''dipe'irca) In the presence of a hydrocarbon (preferably Gengyuan) medium, the polymorph of the compound Ia referred to herein as polymorph is subjected to a plurality of heating and cooling cycles. 'In a further embodiment, the present invention provides a compound for preparation. A method for purifying f crystal form 1V, which comprises preparing ethyl acetate for compound la: adding C5_C7 compound hydrocarbon or hydrocarbon to four liquids to crystallize compound la as purified polymorph IV. 126639.doc 1345566 In another embodiment, the invention provides a pharmaceutical formulation comprising a purified polymorph of Compound Ia and a pharmaceutically acceptable excipient. In another embodiment, the invention provides a pharmaceutical formulation. A purified polymorph containing Compound la and a pharmaceutically acceptable excipient.

The present invention further provides: a method of treating a disease in which gastric motility is attenuated, the method comprising administering to a subject in need of such treatment a purified polymorph IV of a therapeutically effective amount of Compound U; Form IV, purified polymorph IV of a compound for the treatment of a disease with attenuated gastric filling; purified polymorph IV of compound Ia for use in the preparation of a medicament for the treatment of a disease with attenuated gastric sin; and A pharmaceutical composition for treating a disease in which gastric latitude is attenuated, comprising purified polymorph IV of Compound Ia. The present invention further provides a method for treating a disease in which gastric motility is attenuated. The method comprises the step of administering to a subject in need of such treatment a therapeutically effective amount of a purified polysaccharide of the compound & Polymorph II; purified polymorph of compound 1 & for the treatment of diseases with reduced gastric peristalsis; purified polymorph of compound Ia for use in the preparation of a drug for the treatment of diseases with reduced gastric sphincter; And a pharmaceutical composition for treating a disease in which gastric stenosis is attenuated, comprising a purified polymorph II of compound 13. Examples of descriptive conditions for diseases with reduced gastric sinus include, but are not limited to, gastropares' gastroesophageal tract Countercurrent disease ("GERD"), anorexia, gallbladder stasis, postoperative hemorrhagic bowel obstruction, scleroderma, pseudo-intestinal obstruction, colonic irritability, gastritis snoring and chronic constipation (colon weakness). The polymorph of the invention is particularly effective in the treatment of GERD. [Embodiment] 126639.doc 1345566 夕日曰1 was characterized as a predominantly amorphous white powder, which was determined to be poorly crystallized by XRPD. It exhibits a 85% weight gain between 〇 and 9〇〇/〇 RH (relative humidity) for relative moisture absorption. The thermal analysis shows an endothermic peak between the ambient temperature and 9 归因 due to the loss of the mixture. The weight loss with heat absorption was 3.0% (corresponding to 1.4 m water). When heated to a temperature of 75 ° C and 1 〇〇 C, the '彡 crystal form' loses crystallinity. Multi-B 曰 1 is converted to a second polymorph called polymorph II under aqueous conditions. The latter two observations, 'The results of the selection of polymorph j as a polymorph for the development of the formulation have an adverse effect. Representative XRPD, DSC and GVS data for polymorph 1 are shown in Figures la, 2a and 33, respectively. The Dominant II feature is a white private cell with a small particle size (<1〇 μιη) and no discernable morphology. XRPD shows that the polymorph π is a day with a certain amorphous content. When held between 5% (10) and RH, the polymorph type showed a 4% weight loss, equivalent to 2 moles of water per mole of compound (Ia). As evidenced by XRPD reanalysis under ambient conditions, there is a corresponding crystalline loss "' indicating that the polymorphic hydrazine is a dihydrate. Thermal analysis showed a broad endothermic peak between ambient temperature and l 〇〇 ° C due to solvent (water) loss. This loss corresponds to a 5.0% weight loss' equivalent to 25 moles of water and the additional water content can be attributed to polymorph II hygroscopicity. At 5 "c and 75. There is a loss of crystallinity between the crucibles. Polymorph II is at 30. . The crystallinity was also lost during the vacuum drying. The representative XRPD, Dsc and Gvs data of polymorph II are shown in the graph, the pores and Fig. 3b, respectively. The characteristic of the IV is 4 〇μηη. The white powder XRPD of the particle size and needle form shows crystallization. Its water solubility is m. 126639.doc •14- 1345566 At 97.9% purity, polymorph IV is not highly hygroscopic, at 〇% rh and 90% RH There is a 3.5% weight increase between them. When subdivided under ambient conditions, the weight increase does not result in a change in the XRPD pattern. Thermal analysis shows that there is a wide endotherm due to solvent (water) loss (1.5% weight loss). The peak is between the ambient temperature and 65 ° C. The melting transition starts at 15 ° C, and the xrpd pattern does not change when heated to melt. At 75% rh, 4 〇. Storage for 10 weeks and in solubility No significant changes were observed during the analysis. The crystallinity retention and storage stability during heating made the polymorphs a good candidate for the development of pharmaceutical formulations. Representative XRPD, DSC and polymorph IV The GVS data is shown in Figure 1 (1 'Figure 2c and The representative FT-IR, FT-Raman, solid nmr and N solid state NMR data of polymorph IV are shown in Fig. 5, Fig. 6, Fig. 7 and Fig. 8, respectively. Mistaken by aging in a diisopropyl test (repeated heating and cooling cycles) from the preparation of polymorph II. It is also possible to use a Cs-C7 alkane or olefin such as (preferably) heptane - the material thus produced is initially Contains a number of crystal forms π, however, the polymorph „ is removed after drying under vacuum (as measured by xRpD). The number of cycles is at least 2, preferably 3, but a larger number of cycles can also be used (eg, Up to 12 cycles) The temperature range of the cycle is usually between 5 in the 24-hour period (between 50 and 50, preferably between the brother and the sister). In addition, the compound la is also found. Several other polymorphs, the preparation and characteristics of these other polymorphs are summarized below. For various reasons, these polymorphs are not as suitable for formulation development as polymorphs II and IV. Polymorph III is in DIPE. Polycrystal obtained after aging of compound 1 & amorphous stearate (repeated heating and cooling cycles) This polymorph could not be separated when 126639.doc -15 · 1345566 enlarged scale and no further study. Fig lc shows a representative XRPD of polymorph Form III data.

Polymorph V was prepared by aging in a third butyl methyl ether ("TBME"). Polymorph V is characterized as a white powder having a small particle size (<10 μιη) and no definable morphology. XRPD showed polymorph V to be crystalline and its water solubility was 0.72 mg/mL. Thermal analysis shows the melting transition initiated at 100 °C. This correlates with the 8.7% weight loss exhibited by TGA (equivalent to 1 mole TBME), indicating that polymorph V is a mono TBME solvate. The polymorph V crystallinity decreased after one week of storage at 40 ° C and 75% RH and was converted to polymorphic hydrazine during the solubility analysis. Polymorph V is a solvate that adversely affects the desire to develop candidates for formulation development. Representative XRPD and DSC data for polymorph V are shown in Figure le and Figure 2d, respectively.

Polymorph VI is a partially crystalline polymorph obtained from ethyl acetate, isopropyl acetate or anisole. A small step weight loss was observed during thermogravimetric analysis (TGA), indicating that polymorph VI is a family of iso-structural solvates. The endotherm of the ethyl acetate derived form was 1 〇 7 ° C; the corresponding starting form of isopropyl acetate was 90 ° C. The anisole form has two endothermic peaks starting at 98 ° C and 110 ° C. Polymorph VI was converted to polymorph IV after storage at 40 ° C, 75% RH or converted to polymorph IV or II during solubility analysis. The conversion of polymorph VI to polymorph IV indicates that polymorph VI is not stable enough to be developed for the formulation: the candidate. Representative XRP0, DSC and GVS data for multiple 'Form VIs (in ethyl acetate form) are shown in Figures If, 2e and 3d, respectively. 126639.doc •16- 1345566

Polymorphic Form VII is obtained after aging in toluene. Polymorph Form VII is characterized as a white powder having a small particle size (<20 μιη) and no discernible morphology. XRPD shows that it is partially crystalline. Its water solubility is 0.75 mg/mL. Polymorph VII exhibits a constant weight loss in the analysis of the "gravimetric vapor sorption, GVS" and exhibits a corresponding loss of crystallinity based on XRPD reanalysis under ambient conditions. Thermal analysis is shown at 103 °C. The melt transition, with a 4.7% weight loss exhibited by TGA, corresponds to 0.5 moles of benzene. Thus, it appears that polymorph VII is a hemi-toluene solvate. Polymorph VII at 40 ° C Loss of crystallinity after storage for one week at 75% RH, and conversion to a mixture of polymorphs II and IV during solubility analysis. Polymorph VII is a solvate and its instability makes it suitable for formulation development. Secondary candidates. Representative XRPD, DSC, and GVS data for polymorph VII are shown in Figures lg, 2f, and 3e, respectively.

Figure lb shows a representative XRPD pattern of polymorph II. Table 1 is a list of the main peaks in Figure lb. Thus, in one aspect, polymorph II can be characterized by a characteristic XRPD peak at 3.5 ± 0.1, 6.9 ± 0.1, 9.2 ± 0.1, 9.6 ± 0.1, and 10.4 ± 0.1 degrees 2 ,, or by 3. 5 ± 0 · 1,6·9±0·1, 9·2±0·1, 10.4±0.1, and 18.0. The characteristic XRPD peak at 0.1 degree 2Θ is defined. Table 1 XRPD data of purified polymorph II of compound la. Peak number 2 Θ angle (degrees) relative intensity (%) 1 3.5 22.5 2 6.2 12.7 3 6.9 100.0 4 7.9 18.0 126639.doc -17- 1345566

5 8.5 12.7 6 9.2 26.2 7 9.6 47.7 8 10.4 23.4 9 11.0 14.2 10 11.9 13.0 11 12.4 16.5 12 13.8 19.2 13 14.7 15.4 14 15.2 17.9 15 18.0 22.9 16 19.5 31.4 17 21.8 29.4 18 22.6 17.5 Figure ld shows polymorph 1V Representative XRPD_. Table 2 is a list of the main peaks in Figure Id. Thus, in one aspect, polymorph IV may be characterized by a characteristic XRPD peak at 3.8 ± 0.1, 7.5 ± 0.1, 8.1 ± 0.1, 9_6 ± 0.1, and 11. 〇 ± 〇 1 ° 20 or by 3.8 The characteristic xrpd peak at 0.1, 7.5 soil 0.1, 16.1 soil 0.1, 16.5 ± 0.1 and 17.1 soil 0.1 degree 2 来 is defined.

Table 2 XRPD data of purified polymorph IV of compound la. Peak number 2 Θ angle (4) Relative intensity (%) 1 3.8 52.3 2 6.5 20.7 3 7.5 33.3 4 8.1 45.7 5 8.9 15.9 6 9.6 100.0 126639.doc • 18 · 1345566 7 11.0 83.0 8 11.3 28.1 9 12.2 27.2 10 13.0 25.8 11 13.3 31.8 12 13.6 25.0 13 14.4 25.6 14 15.4 25.5 15 16.1 37.4 16 16.5 43.2 17 17.1 39.5 18 17.4 38.5 19 19.3 31.4 20 20.2 28.6 21 21.1 38.0 22 21.8 20.9 23 22.2 23.7

Figure 2c shows a representative DSC scan of polymorph IV. (In this example, the sample of polymorph IV was prepared from DIPE according to Example 4). Polymorph IV exhibits a broad endothermic peak between ambient temperature and u〇〇c due to solvent loss, followed by 143. 〇156. (: starting and at 149. 〇 161. (: minimum melting endothermic peak. This endothermic peak is absent in other polymorphs of the identified compound Ia. Therefore, in one aspect, polymorph IV can Characterized by a melting endotherm peak having an onset temperature between about 143 ° C and about 156 ° , to distinguish it from other polymorphs of compound la. Figure 3c shows a constant temperature at 25 ° C A representative GVS scan of polymorph IV. Polymorph IV exhibits a 3.5% mass uptake between 〇% RH and 90% RH. Mass gain/loss is extremely 126639.doc after multiple adsorption and desorption cycles • 19-1345566. Polymorph I (Fig. 3a), polymorph (Fig. 3b) and polymorph VI (Fig. 3d) exhibit a mass of 6% to 10% between 0% RH and 90% RH. Ingestion, and its mass gain/loss changes drastically after multiple adsorption and desorption cycles. Polymorph VII (Fig. 3e) exhibits a 3% mass uptake between 〇% rh and 90% RH, but its quality is obtained / The loss also changes dramatically after multiple adsorption and desorption cycles. Thus, in one aspect, polymorph IV can be characterized as between 〇〇/〇RH and 90% RH (25°C) It has a 3.5% mass uptake and has consistent quality gain/loss after multiple adsorption and desorption cycles.

Figure 5 shows a representative FT-IR scan of polymorph IV. The following main absorption bands can be noted (cnTkss strong, m=middle, w=weak, experimental error +/-2 cm.1): 3381(m), 2973(m), 2936(m), 1721(m) , 1674(m), 1558(w), 1450(m), 1408(w), 1375(m), 1347(m), 1325(w), 1272(w), 1250(w), 1176(s) ,

1167(s), 1130(w), ll〇8(s), 1080(w), 1053(w), 1038(w), 1029(w), 993(s), 982(w), 958(m) ), 930(w), 898(m), 864(w), 844(w), 833(w), 804(w), 778(w), 753(w), 724(w), 701(w ) and 668(w) » The following peaks are particularly unique: 1558 (w), 1347 (m), 1130 (w), 1108 (s) and 993 (s). Figure 6 shows a representative FT-Raman scan of polymorph IV. It can be noted that the following main Raman shifts = extremely strong, s = strong, m = middle, w = weak, experimental error is +/- 2 cm · 1) : 2977 (vs), 2940 (vs), 2916 (m) , 2848(s), 2719(m), 1726(w), 1662(w), 1463(s), 1412(w), 1374(w), 1356(m), 1330(w), 1282(w) , 1249(w), 1208(w), 1160(m), 1130(w), 1109(w), 126639.doc •20· cs 1345566 1058(w), 1037(w), 1000(w), 983 (w), 960(w), 933(w), 900(w), 865(m), 829(w), 812(w), 773(w), 753(w), 736(w), 670 (w), 615 (w), 527 (w), 486 (w), 460 (w), 433 (w), 407 (w), 346 (w), 279 (w), and 226 (w). The following displacements are particularly unique: 1463(s), 933(w), 736(w), and 615(w).

Figure 7 shows a representative 13C solid state NMR scan of polymorph IV. The following chemical shifts were observed (ppm relative to the external sample of 29.5 ppm adamantine, intensity equivalent to the peak height in parentheses): 177.6 (4.68), 177.3 (3.6), 171.7 (1.18), 170.8 (2.68) ), 103.2 (5.08), 101.2 (5.08) ' 97.1 (5.09) ' 95.7 (6.76) , 85.6 ( 2.27 ) ' 80.3 ( 2.72 ) , 78.2 ( 6.35 ) , 77.4 ( 5.09 ) , 77.1 ( 5.42 ) , 76.4 ( 11.6 ) ) ' 74.7 (7.69), 74.1 (9.97), 73.9 (10.11), 73.4 (4.39), 72.1 (2.62), 71.6 (6.35), 71.2 (5.61), 69.8 (1.75), 69.5 (4.22), 68.8 (5.34) ), 68.4 (4.79), 66.0 (5.13), 65.3 (5.72), 62.0 (2.31), 52.9 (2.59), 51.2 (5.06), 49.5 (5.74), 45.7 (12), 44.4 (5.26),

39.9 (3.58), 36.6 (3.32), 35.6 (3.82) ' 35.5 (3.41), 34.6 (3.29), 34.0 (2.48), 33.5 (5.01), 32.9 (2.86) ' 32.8 (7.31), 32.2 (5.15), 29.4(1.69), 28.4(6.71), 27.1(5.53), 26.2(3.22), 23.6(7.16), 23.3(1.67), 22.6(5.05), 22.3(10.17), 22.1(6.25), 21.9(4.88), 21.4(7.3) ' 21.2(6.22) ' 20.6(7.42) ' 20.5(8.01) ' Γ9.9(9.82), 19.5(2.79), 19.2(6.23), 18.9(7.85), 18.4(2.93) > 17.8( 5.67), 12.7 (6.44), 11.6 (4.1), 126639.doc • 21 - 1345566 11-3 (5.13), 9.6 (6.09) and 7.7 (7.11). The following chemical shifts are especially unique: 177.6, 170.8, 45.7, 28.4, 12.7 and 7.7 ppm. Figure 8 shows a representative 15n solid state NMR scan of polymorph iv. The following chemical shifts were observed (ppm relative to the external sample of DL-alanine of _331 5 pprn, intensity equivalent to the peak height in parentheses): -270.8 (4·29), -273.4 (12 ), -342.4 (8.16) and -345.1 (9.27).

The polymorph of the present invention may be used in combination with lozenges, pills, capsules, suppositories, pessaries, solutions, emulsions, suspensions, and any other non-toxic, pharmaceutically acceptable carrier commonly used in the preparation of the compounds la In. Polymorph IV is particularly preferred for use as a bulk drug (drUg substance) and for the operational purposes of solid formulations. Excipients which may be used include carriers, surfactants, thickeners or emulsifiers, solid binders, dispersing or suspending aids, solubilizers, colorants, flavoring agents, coatings, disintegrating agents, lubricants, Sweeteners, preservatives, isotonic agents, and combinations thereof. Selection and use of suitable job agents taught by Gennaro Remington: The Science and Practice of Pharmacy, %

(Lippincott Williams & Wilkins 2003), the disclosure of which is incorporated herein by reference. The polymorph of the present invention can be administered orally. Oral administration may involve swallowing, allowing the compound to enter the gastrointestinal tract ' or buccal or sublingual administration' whereby the compound directly enters the bloodstream from the mouth. Formulations suitable for oral administration include solid formulations such as tablets, capsules containing microparticles, liquids or powders, buccal preparations (including buccal preparations for filling liquids), chewables, multiparticulates and microparticles (multi_and) Nano-particulate), gel, solid solution 126639.doc •22·

C S 1345566 Body, liposomes, membranes, ovules, sprays and liquid formulations. Liquid formulations include suspensions, solutions, syrups and elixirs. These formulations may be used as a filler in soft capsules or hard sacs, and usually comprise a carrier (eg water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or a suitable oil) and one or more emulsifiers And/or suspension. Liquid formulations can also be prepared by, for example, reconstituting a solid from a drug capsule. For lozenge dosage forms, the dosage may comprise from i% by weight to 80% by weight of the dosage form, more typically from 5% to 6% by weight of the dosage form, depending on the dosage. % In addition to drugs, tablets usually contain a disintegrant. Examples of disintegrants include sodium glycolate, sodium methylcellulose, methicone, crosslinked methylcellulose, crosslinked polyvinyl ketone, and polyethylene (4) ' Mercapto cellulose, microcrystalline cellulose, low carbon alkyl substituted hydroxypropyl cellulose, starch, pregelatinized starch and sodium alginate. Usually, the disintegrant accounts for 5% to 5% by weight. In one embodiment of the invention, the disintegrant comprises from 5% to 20% by weight of the dosage form. Adhesives are commonly used to impart a cohesive quality to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugar, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropylcellulose, and propylmethylcellulose. Tablets may also contain diluents such as 'lactose (monohydrate, spray dried monohydrate, anhydrous and its like), mannitol, xylitol, dextrose, sucrose, sorbitol, Micro. Octacellulose Starch and Dicalcium Phosphate Dihydrate The tablet may also optionally contain a surfactant (such as sodium lauryl sulfate and polysorbate 80) and a helper (such as a bismuth and bismuth). talc). When present, the surfactant may comprise from 2% by weight to 5% by weight of the bonding agent, and the flow aid may comprise from 2% to 126639.doc • 23 - 1345566 $% to 1% by weight of the tablet . Tablets also typically contain a lubricant such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and a mixture of magnesium stearate and sodium lauryl sulfate. Lubricants typically range from 25% by weight to 1% by weight. In one embodiment of the invention, the lubricant comprises from 5% to 3% by weight of the tablet. Other possible ingredients include antioxidants, colorants, flavoring agents, preservatives, and taste masking agents. Exemplary lozenges contain up to about 80% of the drug, from about 10% to about 9 inches.

A binder of about 5% by weight to about 85% by weight of the diluent, about 2% by weight to about 10% by weight of the disintegrant, and about 0.25 % by weight to about 1% by weight of the lubricant. ° The tablet blend can be compressed directly or by roller to form a tablet. Alternatively, portions of the tablet blend or blend may be wet, dry or melt granulated, (tetra) silk or extruded prior to tableting. The final formulation may be packaged; the s layer may be coated or uncoated; it may even be encapsulated. Η

Lieber- man^L. Lachman^Pharmaceutical Dosage F〇rms.

In T s, Vol.i98〇), the money is widely described, and the crystallization (4) is converted from the compound by another polymorph to “, and the preparation process is purified. In this example, the polymorph in the sample...: relative The amount of polymorph IV in the sample prior to the preparation procedure (which may be zero increased... other impurities may be removed by this purification. Preferably 'purified polycrystalline (iv) contains a predominant amount of polymorph W, Discharge the compound la polymorph. ' 〆, he prepared a purified polymorph 1V - a preferred method is to dissolve the compound Ia in I26639.doc

• 24· 1345566 Acetate in the domain and then add decane or return to polymorph IV crystal β recovery or thinning has a low water content 'preferably lower than G.0G5% W" This procedure for the compound U of acetic acid The water content and crystallization temperature in the vinegar solution are somewhat sensitive. Water may enter the solution via two routes. The compound used [a may be in the form of a polymorphic form with a certain water content (eg polymorph H, a dihydrate) Or the ethyl acetate may contain traces of water. The water content of the solution of the compound h in acetic acid is preferably lower than the pass, more preferably lower than

1.9, the best between 1% and about 9% (vol/vol or v/v). The water content can be maintained at the desired low level by various techniques, individually or in combination: (a) using a polymorphic form of a compound which is not a hydrate. (b) pre-drying the compound Ia used, for example under vacuum At 4 〇. 〇 pre-dry for 17 hours. (4) Use high purity, low water content of ethyl acetate or pre-dry ethyl acetate.

(d) Drying the ethyl acetate solution before adding the Cs-C7 alkane or olefin, for example, drying with anhydrous sodium sulfate. Because of the sensitivity to the water content of the ethyl acetate solution, it is recommended to calculate or characterize the water content of the ethyl acetate solution before adding the Cs-C7 alkane or olefin, and if it is higher than 36%, add the alkane The water content may be lowered prior to the olefin or the crystallization temperature may be from about 20 ° C to about 36. (In the range of:. Typically, when the water content in the ethyl acetate solution is 1.9% or less than 1.9%, a temperature higher than 25t is recommended for the production of polymorph IV' (for example, 25: (to 36). 126 126639.doc •25- 1345566 Examples of suitable CrC® smog or olefins that can be used in the above procedures (or in alternative curing procedures) include: n-pentane, cyclopentane, decene, 2_ Pentene, isopentane, neopentane, n-hexane, 1-hexene, cyclohexane, n-heptane, 1-heptene and the like. n-heptane is preferred. The invention is further understood to be illustrative and not limiting. Example 1 - General Analysis Procedure

XRPD patterns were collected on a Bmkei·AXS C2 GADDS diffractometer using Cu Κα radiation (40 kV, 40 mA), an automated XYZ platform, a laser video microscope for automatic sample positioning, and a HiStar 2D area detector. The X-ray optics consist of a single Giibel multilayer mirror coupled to a 0.3 mm pinhole commator. The beam divergence (i.e., the effective size of the X-ray beam on the sample) is about 4 mm ^ at a given 3.2. The Θ-Θ continuous scan mode is used in the case of a sample detector distance of 2 〇 cm in the range of 29 〇. Typically, the sample is exposed to an X-ray beam for 120 seconds.

XRPD patterns were obtained by Pharmorphix Ltd. (Cambddge, United Kingdom). Using the Cu Κα radiation (4〇kv, 4〇, (4) goniometer, automatic divergence and receiving slits, graphite secondary monochromator and scintillation counter to sample the parent ray powder diffraction pattern on the Siemens D5000 diffractometer The data was collected in a continuous scan mode at an angle range of 2° to 42. 2Θ using a step size of 0.02. 2Θ and a step time of 1 second. The sample was dried at 30 C under vacuum for 24 hours before analysis. However, other drying schemes can also be used. 126639.doc -26- 1345566 XRPD samples that are run under ambient conditions are prepared as flat samples without the use of powders in the absence of grinding. Samples of approximately 25 mg to 50 mg are used. Gently fill the 12 mm diameter, 0.5 mm deep into the cavity in the polished zero-background (510) Shi Xi wafer (The Gem Dugout, 1652 Princeton Drive, Pennsylvania State College, PA 16803, USA). Perform all samples in fixed mode.

GVS data was also collected by Pharmorphix, Ltd. All samples were performed on a Hiden IGASorp Moisture Adsorption Analyzer performing CFRSorp software. The sample size is usually 10 mg. The moisture adsorption-desorption isotherm is outlined as outlined below, with two scans providing one complete cycle, with two scans providing one complete cycle. Load and unload all samples in typical ambient (indoor) humidity and temperature (40% RH, 25 °C). All samples were analyzed by XRPD after GVS analysis. Standard isotherms were performed at 25 ° C at 10% RH intervals over the range of 〇% RH to 90% RH. Scan 1 scan 2 adsorption (%RH) desorption (%RH) adsorption (%RH)

10 20 30 40 40 50 60 70 80 90 85 75 65 45 35 25 15 5 0 126639.doc • 27· 1345566 The water content of ethyl acetate, n-heptane and compound la was determined by the Karl Fischer method. The water content of the compound la/ethyl acetate solution was calculated based on the mass balance and the result was expressed as % v/v.

FT-IR data was acquired using a ThermoNicolet Avatar 360 FTIR spectrometer equipped with a Smart Golden GateTM single-reflection ATR accessory (diamond ATR crystal with zinc selenide optics) and a d-TGS KBr detector. The spectra were collected with a resolution of 2 cm·1 and a co-addition of 256 scans. Use Happ-Genzel apodization. Since the FT-IR spectrum was recorded using a single reflection ATR, sample preparation was not required. The use of ATR FT-IR will make the relative intensity of the infrared band different from the relative intensity of the infrared band visible in the absorbance FT-IR spectrum prepared using KBr round or nujol mull samples. Due to the nature of ATR FT-IR, bands at lower wavenumbers are stronger than bands at higher wavenumbers. Unless otherwise noted, the experimental error is soil 2 crrf1. The peak was picked up using the ThermoNicolet Omnic 6.1a software. The intensity assignment is relative to the dominant band in the spectrum, so the intensity assignment is not based on the absolute value from the baseline measurement. When assessing split peaks, intensity values are obtained from the baseline, but strength is again assigned relative to the strongest band in the spectrum. FT-Raman data was collected using a Bruker Vertex 70 FT-IR spectrometer with a Ramil FT-Raman module equipped with a 1064 nm NdYAG laser and an LN-Germanium detector. All spectra were recorded using 2 crrT1 resolution and Blackman-Harris 4 apodization, 300 mW laser power and 4096 scans. The sample is measured directly from the glass vial of the sample and exposed to laser radiation. The data is presented as an intensity as a function of Raman shift, and 126639.doc -28- 1345566 uses the Bruker Raman Correct function (Bruker Software-OPUS 6.0) to calibrate the instrument using the white light spectrum from the reference lamp Response and frequency dependent scattering. The experimental error was ±2 cm·1 unless otherwise noted. Use the ThermoNicolet Omnic 6. la software to pick up the peaks. The intensity assignment is relative to the dominant band in the spectrum, so the intensity assignment is not based on the absolute value from the baseline measurement. When the splitting peak is evaluated, the intensity value is obtained from the baseline, but the intensity is assigned again relative to the strongest band in the spectrum.

Bruker-Biospin 4 mm CPMAS probe in a standard well (8丨311 (13『(!-1)0 generation) ug 1>111<;61·-Biospin Avance 500 MHz NMR spectrometer under ambient conditions Solid C13 and N15 NMR data were collected. The nitrogen spectra were collected using a 7 mm BL CPMAS probe. The samples were filled in 4 mm and 7 mm Zr02 rotors placed at a magic angle and rotated at 7.0 kHz. The carbon and nitrogen spectra were collected by cross-polarization magic angle spinning (CPMAS). The cross-polarization time was set to 2.5 ms. Approx. 90 kHz (4 mm probe) and 70 kHz (7 mm probe) were applied. The proton decoupling field of the needle. Collect 5120 (13C) and 30,000 (15N) scans. Adjust the recycle delay to 1.5*T1H (where T1H represents the proton-recovered proton relaxation recovery experiment based on proton detection) Calculated proton longitudinal relaxation time.) The carbon spectrum was used to refer to the carbon spectrum using the external standard of crystalline adamantane, and the upfield resonance was set to 29.5 ppm. The external standard of D,L-alanine was labeled with 15% of the crystal. The nitrogen spectrum is mentioned and its resonance is set to -3 31.5 ppm. Example 2 - General procedure for the preparation of compound la As described in the Liu '616 application incorporated herein by reference, 126639.doc _29·1345566 Compound ll is prepared. Figure 7 summarizes the synthetic scheme used. Sodium reduces erythromycin A (1) to produce intermediate (9S)-erythromycin dihydrate A (7). In a base such as sodium acetate or tris(hydroxymethyl)amino decane ("TRIS") Demethylation of (9S)-erythromycin dihydrate A (7) in the presence of N-desmethyl-(9S)-erythromycin dihydrate A (8) in the presence of an alkyl group with 2-iodopropane This further produces intermediate 9. The alkylation of intermediate 9 with N-methylbromide produces compound Ia. The polymorph of compound la obtained will depend on the separation and purification steps after the chemical reaction.

The preparation of the intermediate 9 is also described in US 6,946,482 B2 (2005) to San U. et al., which is incorporated herein by reference. The step of de-mersing is also described in U.S. Patent Application Serial No. 11/591,726, the entire disclosure of which is incorporated herein by reference. Example 3 - Preparation of Compound la and Separation of Polymorph I Form

<THF" The solution in 1,800 mL) was injected into a 5 liter three-necked round bottom flask equipped with a mechanical stirrer and an internal thermocouple temperature probe. A solid potassium tert-butoxide (25.3 g, 226 mmol '1.1 eq.) was added in one portion with nitrogen. The reaction mixture was stirred at 〇 ° C for 1 hour. Thin layer chromatography (1:2 hexane-acetone eliminator) showed completion of the reaction. The reaction was stopped by adding a saturated NaHC03 solution (300 mL). The mixture was partitioned between dilute NaHc 3 (25 mL) and ethyl acetate ("EtOAc ", < The aqueous layer was extracted with EtOAc (2×l, 500 mL). The combined organic layer is dried. Obtained crude compound Ia (178 丨g) as a pale yellow solid, which was then purified on 矽126639.doc -30- 1345566 (2,800 g of phthalocyanine, 20 to 40% acetone in hexane, 1 〇/〇3 Ethylamine) to afford pure compound Ia (135 g, 79% yield). To remove traces of solvent and triethylamine, the above product was repeatedly dissolved in dioxane and subjected to four rotary evaporation cycles followed by drying under high vacuum. It was then lyophilized with acetonitrile-water (1:1 Wv, 4 mL/g) and dried in a vacuum oven (16 h, 50 〇 to provide the final product (mp 〇 6 ° C measured by capillary melting point apparatus) -108t:) This procedure yields a compound la in the form of a polymorph (note that approximately 11 Å in the DSC of polymorph I in Figure 2a <>> (slightly endothermic): Liu '61 6 application The report reports a melting point, thus indicating the polymorphism described in this section. Example 4·Preparation of compound la and polymorphism] Separation of Form 9 Compound (light orange material, 353 g, 462 mm〇i) & N•Bromoacetamide (84 g, 600 mmol, 1.3 eq) was dissolved in THF (3 9 L, anhydrous and free of inhibitors). The yellow solution was cooled to 〇 ± 2 t over 2 min in THF ( 549 mL, 549 mmo 1.2 eq.)^ Dilute with J ]^ potassium butoxide to maintain the temperature between 0 ° C and 3 ° C. Continue stirring at 0 ± 2 ° C while using the process (in- Process) HPLC monitors the progress of the reaction for the disappearance of the starting material. After 15 minutes, only about 〇34〇/〇 of the starting material is left.

NaHC〇3 (2.6 L) stopped the reaction. The layers were separated and the combined aqueous layers were extracted with EtOAc (EtOAc) (EtOAc) eluted with water (1.sup.2L), followed by brine (12 L). The organic phase was dried over MgSO4 (75 g). The desiccant was rinsed with Et.sub.2Ac (200 mL). The combined filtrate was concentrated to yield compound Ia (392 g) as pale yellow residue. The residue was dissolved in acetone (3.1 L, 8 mL/g) and used Deionized water 126639.doc -31 - (3.1 L) Dilute the pale yellow solution. Cool the slightly turbid solution to 〇C to 5C in 2 minutes and produce a precipitate (approximately 1 〇〇c visible crystal). 〇5<>c The suspension was stirred for 15 minutes and diluted with additional deionized water (31 L) over 30 minutes, then at 〇t to 5. The mixture was stirred for 3 minutes. The solid was separated by filtration, followed by C. A mixture of hydrazine (0.15 L) and deionized water (0.30 L) was washed with a dry solid (about 16 hours) and then dried (3 〇, 〇, 29 " Hg) for 64 hours to provide a compound as an off-white solid. Ia (322 g). Example 5 - Preparation of polymorph IV

DIPE (1.0 mL) was added to compound (Ia) polymorph 11 (250 mg) in a small screw cap vial. The vial and its contents were subjected to three heating and cooling cycles between ambient temperature and 50 °C over a period of 24 hours. The resulting solid was filtered and analyzed by xRPd after drying at 3 CTC for 24 hours to show that it had been converted to polymorph IV.

1H_NMR analysis of the polymorph IV thus obtained showed the presence of a trace amount (〇_9%, 0.07 equivalent) of DIPE. DIPE was removed by slurrying in water as follows: Water (1. 〇 mL) was added to sample polymorph IV (30 mg) in a small screw cap vial and shaken at 25 C for 72 hours. The resulting solid was filtered and dried. Analysis of XRPD and 1H-NMR showed that the dipe had been removed without changing the form of the sample. Example 6 - Alternative Preparation of Polymorph IV Compound Ia (2.0 g) was dissolved in ethyl acetate (12 mL) at ambient temperature. The water content of the ethyl acetate solution was 1 · 丨 % v / v. The pale yellow solution was placed in a 500 mL three-necked round bottom flask equipped with an overhead stirrer (1KA RW16 basic) at 32. (: Stir the solution at 180 rpm to 185 rpm and make 126639.doc •32· 1345566

An n-geptane (8 〇 mL) was added at a rate of 0.8 mL/min using a syringe pump (KdScientific). The heptane addition was interrupted for 4 minutes after the addition of 50 mL of heptane to refill the syringe. After further adding 30 mL of heptane (for example, a total amount of 80 mL), the resulting suspension was further stirred at 185 rpm and at 32 ° C for 2.5 hours. The suspended polymorph IV crystals were collected by using a ceramic 5 cm Buchner funnel and Whatman #4 filter paper. The crystals were rinsed with 90:10 v/v heptane: ethyl acetate (2 〇 mL) and air dried for 10 minutes. The crystals were further dried under vacuum (29 5 " Hg) at 40 ° C for 16 hours to give i_62 g polymorph iv. The product was confirmed to be polymorph I v by Dsc and XRPD. Repeating the experiment at 25 °C also produced polymorphic iV (only a slightly lower yield). Example *7 - Another alternative preparation of polymorph IV This example describes the preparation of polymorph Iv by aging in n-heptane. Add Zheng Gengyuan (500 pL) to the polymorph type in the small screw cap vial. The vial was subjected to a sub heating/cooling cycle of enthalpy between 4 and 24 Torr over a period of 24 hours with stirring. XRPD analysis confirmed that the polymorph was produced. The same program can be executed with DIPE.

The foregoing [embodiments] of the present invention include paragraphs that are mainly or only associated with a particular portion or aspect of the present invention. It is understood that this is for the purpose of clarity and convenience, and the specific features are not only related to the paragraphs in which the particular features are disclosed, and the disclosure herein includes all suitable combinations of the information seen in the different paragraphs. Similarly, although the various figures and descriptions herein are directed to particular embodiments of the invention, it is understood that the particular features may be Features are used in the context of another diagram or embodiment, or are generally used in: 126639.doc -33- 1345566 Inventive. Furthermore, although the invention has been particularly described with respect to certain preferred embodiments, the invention is not limited to the preferred embodiments. Rather, the scope of the invention is defined by the scope of the appended claims. [Simple description of the diagram] Figure la, Figure lb, Figure lc, Figure ld, Figure le, Figure lf and Figure 1 § show the polymorph of compound la respectively! , „, m, IV, v, VI (in ethyl acetate form) and VII X-ray powder diffraction ("xrpd") pattern.

Figures 2a, 2b, 2c, 2d, 2e, and 2f show the difference between the polymorphic ϊ, „, IV, v, VI (ethyl acetate form) and νπ of the compound la (&quot ;DSC") scan chart. Figures 3a, 3b, ", 3d and 3e show compounds, respectively. Multi-crystal form I, π, iv, VI (in ethyl acetate form) and νπ measured heavy vapor adsorption ("GVSM" scan. Figure 4 shows a synthetic scheme for the preparation of compound 13.

Figure 5 is a representative FT_IR (Fourier Transform Infrared) scan of the polymorph type. Figure 6 is a representative FT-Raman scan of polymorph IV. Figure 7 is a representative 13C solid state NMR scan of polymorph IV. Figure 8 is a representative 15N solid state NMR scan of polymorph IV. 126639.doc -34-

Claims (1)

1345566 • · Patent Application No. 096146166 /. Beer r month i«y 日修 (more) original notice -_ 1 A Chinese patent application scope replacement (May 1st) "X. Patent application scope: A compound having the structure represented by formula la Purified polymorph ιν, It is characterized by using a copper ruthenium-αι X-ray (wavelength = 154 〇 6 angstroms) to obtain XRPD peaks at 3.8, 7, 5, 16.1, 16.5 and 17.1 degrees 2 Θ (± 0.1). A method for producing a purified polymorph IV of a compound having the structure represented by Formula 1 & as claimed in the claims, which comprises subjecting the polymorph II of the compound to a diisopropyl ether And at least two heating and cooling cycles in the presence of a medium of C5_C7 alkene or an alkene, wherein the polymorph type is characterized by using copper Κ·αι X-ray (wavelength=1 54〇6 angstrom) to obtain at 3 5, 6.9, 9.2, 10.4, and 18.0 degrees 29 (±0.1): ?(1^>1) peaks, and wherein the heating and cooling cycles have a temperature range of 5 to 5 Torr. Hey. 3. The method of claim 2, wherein the medium is heptane. 4_ A method for preparing a purified polymorph IV of a compound having the structure represented by Formula 1 & as claimed in claim 1, which comprises preparing an ethyl acetate solution of the compound, and adding a C5_C7 alkane or alkene to the solution In order to crystallize the compound into a purified polymorph ιν, wherein the c5_C7 calcined or diluted water content is less than 0.005% Wv, the water content in the ethyl acetate solution is less than 3.6%, and Cs-C7 alkane is added. Or alkene to cause a crystallization system to be carried out between about 2 〇〇c and about 126639-1000519.doc 5. 36 ° C. The method of claim 4, basin 6· Wherein the C5-C7 alkane or alkene is heptane. For example, clear item 4 or request item 5 starts from #曰A. The method wherein C5_C7 alkane or alkene is added to the knot is about 25C and about 36. Between 〇. A method of claim 4 or claim 5 # ^ ^ whistle, wherein the water in the solution is at 1.9% ν/ν. The method of claim 4: claim 4 or claim 5, further comprising the step of determining the water content of the solution, if the water content is higher than 36% wv, reducing the water before adding the CrC7 alkane or woman content. 9. A pharmaceutical formulation comprising: a purified polymorph IV of a compound having the structure represented by formula (10) and a pharmaceutically acceptable form as defined in claim k. The use of purified polymorph IV of a compound of the structure shown is for the preparation of a medicament for the treatment of a disease with impaired gastric peristalsis. 11. The use of claim 1 wherein the disease with reduced gastric peristalsis is gastroesophageal reflux disease (GERD). 12. Purified polymorph IV of a compound of the structure of claim 1 having the structure represented by formula Ia, which is for use as a medicament. 3. The purified polymorph IV of the compound of the structure of the formula 1 having the structure represented by the formula IA is used for the treatment of gastroesophageal reflux disease (GERD). 14. Purified polymorph iv of a compound having the structure represented by formula la, 126639-1000519.doc 1345566 It has essentially 3.8 '6.5, 7.5, 8.1, 8.9, 9.6, 11.0, 11.3, 12.2, 13.0, 13.3, 13.6, 14.4, 15.4, 16.1, 16.5, 17.1, 17.4, 19·3, 20.2, 21.1, 21.8 And an XRPD peak of 22.2 degrees 2 Θ (±0.1). 126639-1000519.doc